Molecular Mechanism of Wendantang Against Schizophrenia in Rats： An Exploration Based on miRNA-219， NR2B， DISC1 and CaMKⅡγ / 中国实验方剂学杂志

ObjectiveTo study the effects of Wendantang on the expression of miRNA-219， N-methyl-D-aspartate receptor 2B （NR2B）， disrupted in schizophrenia 1 （DISC1）， and Ca2+/calmodulin-dependent protein kinase Ⅱγ （CaMKⅡγ） in the frontal lobe of rats with schizophrenia. MethodSixty rats were randomly divided into six groups， namely normal group， model group， high-， medium-， and low-dose Wendantang groups， and clozapine group， with 10 rats in each group. Rats in high-， medium-， and low-dose Wendantang groups were intragastric with 40， 20， and 10 g·kg-1 Wendantang， and the ones in clozapine group were intragastric with 0.02 g·kg-1 clozapine， those in normal and model group were intragastric with equal volume of normal saline， once a day. After 21 days of administration， rats in all groups except for the normal group were injected with 0.6 mg·kg-1 dizocilpine maleate （MK-801） into the left abdominal cavity for inducing acute schizophrenia. The stereotypic behavior and ataxia in rats were scored according to SAMS and HOFFMAN criteria. The morphological changes in the prefrontal cortex were observed by hematoxylin-eosin （HE） staining. The protein expression levels of NR2B, DISC1 and CaMKⅡγ in the frontal lobe was detected by Western blot. The mRNA expression levels of miRNA-219 was detected by real-time fluorescence quantitative polymerase chain reaction（Real-time PCR）. ResultCompared with normal group， the model group exhibited significantly increased stereotypic behavior and ataxia scores （P<0.01）， karyopyknosis and karyolysis in most neurons of the prefrontal cortex， and down-regulated NR2B， DISC1， and CaMKⅡγ protein expression （P<0.01） and miRNA-219， NR2B， DISC1， and CaMKⅡγ mRNA expression （P<0.01）. Compared with model group， Wendantang high-， medium-， and low-doses group lowered the scores of stereotypic behavior and ataxia at 50， 60 mmin（P<0.05，P<0.01）. In high- and medium-dose Wendantang groups， the neurons in the prefrontal cortex were densely arranged. The karyopyknosis and karyolysis were alleviated to varying degrees. The NR2B protein expression in the frontal lobe was up-regulated （P<0.01）. In the medium- and low-dose Wendantang groups， the DISC1 protein expression in the frontal lobe was up-regulated （P<0.05，P<0.01）. Wendantang at each dose significantly increased the CaMKⅡγ protein expression （P<0.05） and miRNA-219， NR2B， DISC1， and CaMKⅡγ mRNA expression in the frontal lobe （P<0.05，P<0.01）. ConclusionWendantang improves the scores of stereotypical behavior and ataxia， relieves the karyopyknosis and karyolysis of neurons in the prefrontal cortex， and increases the expression levels of miRNA-219， NR2B， DISC1， and CaMKⅡγ of rats with schizophrenia， so as to alleviate the schizophrenic-like symptoms and schizophrenia.

Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice / 神经科学通报·英文版

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N

Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice / 神经科学通报·英文版

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-N

Disrupted-in-Schizophrenia-1 SNPs and Susceptibility to Schizophrenia: Evidence from Malaysia

OBJECTIVE: Even though the role of the DICS1 gene as a risk factor for schizophrenia is still unclear, there is substantial evidence from functional and cell biology studies that supports the connection of the gene with schizophrenia. The studies associating the DISC1 gene with schizophrenia in Asian populations are limited to East-Asian populations. Our study examined several DISC1 markers of schizophrenia that were identified in the Caucasian and East-Asian populations in Malaysia and assessed the role of rs2509382, which is located at 11q14.3, the mutual translocation region of the famous DISC1 translocation [t (1; 11) (p42.1; q14.3)]. METHODS: We genotyped eleven single-neucleotide polymorphism (SNPs) within or related to DISC1 (rs821597, rs821616, rs4658971, rs1538979, rs843979, rs2812385, rs1407599, rs4658890, and rs2509382) using the PCR-RFLP methods. RESULTS: In all, there were 575 participants (225 schizophrenic patients and 350 healthy controls) of either Malay or Chinese ethnicity. The case-control analyses found two SNPs that were associated with schizophrenia [rs4658971 (p=0.030; OR=1.43 (1.35-1.99) and rs1538979-(p=0.036; OR=1.35 (1.02-1.80)] and rs2509382-susceptibility among the males schizophrenics [p=0.0082; OR=2.16 (1.22-3.81)]. This is similar to the meta-analysis findings for the Caucasian populations. CONCLUSION: The study supports the notion that the DISC1 gene is a marker of schizophrenia susceptibility and that rs2509382 in the mutual DISC1 translocation region is a susceptibility marker for schizophrenia among males in Malaysia. However, the finding of the study is limited due to possible genetic stratification and the small sample size.

Sinaptogénesis y esquizofrenia: rol de la proteína DISC 1 / Synaptogenesis and Schizophrenia: The role of DISC 1 protein

El presente trabajo aporta información respecto del posible rol en la esquizofrenia del gen DISC 1 y la proteína que este gen codifica. Se realiza un recorrido desde el hallazgo de la translocación cromosómica que llevó a su descubrimiento, hasta la perspectiva actual, que lo conceptualiza como un modulador funcional complejo. La mencionada translocación fue originariamente identificada en una familia escocesa, y se observó que cosegregaba con esquizofrenia y otros trastornos mentales. Actualmente, se considera a DISC 1 como una proteína central dentro de una red de interacciones con otras proteínas - lo que en varios trabajos se denomina interactoma -, tales como NDEL 1, LIS 1 y PDE 4B, entre otras.

This paper provides information regarding the possible role in schizophrenia of the DISC 1 gene and the protein it encodes. It is a tour from the discovery of the chromosomal translocation that led to its discovery, up to the current perspective, which is conceptualized as a complex functional modulator. The above translocation was originally identified in a Scottish family, and it was noted that it cosegregated with schizophrenia and other mental discorders. Currently, DISC 1 is considered as a central protein within its network of protein interactions (named as interactome in several papers), such as NDEL 1, LIS 1 and PDE 4B, among others.

A Disrupted-in-Schizophrenia 1 Gene Variant is Associated with Clinical Symptomatology in Patients with First-Episode Psychosis

OBJECTIVE: DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis. METHODS: Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects. RESULTS: Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p<0.05) higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers. CONCLUSION: DISC1 gene variations may modulate the clinical severity of the psychosis at the onset of the disorder.

Association study between disrupted in schizophrenia 1(DISC1)gene polymorphism and schizophrenic and different subtype depressive patients / 中华行为医学与脑科学杂志

Objective To explore the association between disrupted in schizophrenia 1(DISC1) genepolymorphism and schizophrenia and different subtype depression.To verify if DISC1 gene is the common predisposing gene for schizophrenia and depression.Methods The genotypes and alleles in 260 cases of schizophrenicpatients,96 cases of depressive patients with psychotic symptoms,124 cases of depressive patients without psychotic symptoms,and 100 normal controls were examined with polymerase chain reaction(PCR),denaturing polyacrylamide gel elcctmphoresis separation technique.The association was analyzed between DISC1 gene single nncleotide polymorphisms(SNP) locus rs821616 and schizophrenia and different subtype depression.Results The frequeneies of the genotypes T/T,A/T,and A/A were 3.5%,28.0%and 69.5%respectively,the frequencies of alleles T and A were 9.6%and 90.4% respectively in schizophrenia group.The frequencies of the genotypes T/T,A/T,and A/A were 3.1%,24.0% and 72.9% respectively,the frequencies of alleles T and A were 15.6% and84.4% respectively in depression 1 group;The frequencies of the genotypes T/T,A/T,and A/A were 2.4%,23.4% and 74.2% respectively,the frequencies of alleles T and A were 15.3% and 84.7% respectively in depression 2 group;The frequencies ofthe genotypes T/T,A/T,and A/A were 1.0%,16.0% and 83.0% respectively,the frequencies of alleles T and A were 17.0% and 83.0% respectively in control group.There were significant differences in the frequencies of the genotypes (Chi-Square=8.072,P=0.045)and alleles(Chi-Square=8.564,P=0.036) of DISC1 gene among the four groups with non-parametric Kruskal-Wallis test.After pairwisecomparison each other in the four groups we found that there were significant differences in the frequencies of thegenotypes(Z=-2.802,P=0.005)and alleles(Z=-2.837,P=0.005) of DISC1 gene between patients withschizophrenia and normal controls with non-parametric Mann-Whitney test(two-tailed),there were no significantdifferences between other groups(P>0.05).Conclusion Our results suggest that DISC1 gene polymorphism is associated with schizophrenia significantly,but it is not associated with different subtype depression.This finding do not support the viewpoint that DISC1 gene is the common predisposing gene for schizophrenia and depression.

Association Study of the Disrupted in Schizophrenia 1(DISC1)Gene Polymorphisms with Schizophrenia / 中国心理卫生杂志

T,P=0.008; Genotype:P=0.031)of DISC1 gene were significantly associated with schizophrenia.The haplotypes constructed by these two markers were significantly associated with schizophrenia,such as AT(?2=7.065,P=0.008,OR=1.42,95%CI=1.10~1.83)and GA(?2=6.009,P=0.014,OR=0.80,95%CI=0.68~0.96).When the subjects examined with the positive and negative syndrome scale(PANSS),the risk haplotype AT was not significantly correlated with positive,negative,excitement,depression and cognitive impairment factors of PANSS. Conclusion:These findings provide further evidence for DISC1 as a predisposing gene involved in schizophrenia in the Chinese Han Population.However,no positive association is found between DISC1 polymorphisms with schizophrenia clinical symptoms.